Multiple myeloma (MM) is the second most frequent blood disorder in the United States. Some 13,000 new cases are diagnosed each year. MM is a clonal plasma cell proliferative disease that affects terminally differentiated B cells (i.e. plasma cells). Despite some advances in chemotherapeutic regimens, this disease remains incurable, with a median survival for MM patients of 40 months. Like MM, Monoclonal Gammopathy of Unknown Significance (MGUS) is characterized by monoclonal immunoglobulin in the serum and urine and an increase of monoclonal plasma cells in the bone marrow. However, MGUS patients do not suffer from the clinical manifestations of MM. Importantly, 25% of patients with MGUS progress to myeloma.
It is considered that the cytokine interleukin-6 (IL-6) is a major cytokine that promotes the proliferation of malignant plasma cells in MM. Elevated IL-6 levels are directly correlated with tumor burden, bone destruction, and other tumor-associated activities in myeloma patients (6) suggesting a role for IL-6 in MM. Moreover, some studies have shown that myeloma cells induce IL-6 expression in stromal cells in a largely cell-contact-dependent manner (7). Therefore, the increased levels of IL-6 production likely reflect disease-associated alteration of IL-6 regulation.
The IL-6 gene can be regulated by a variety of factors, including cytokines, IL-1, TNFalpha and, as recently demonstrated, by the NOTCH genes products. The NOTCH genes were originally identified in Drosophila melanogaster and are members of an evolutionarily conserved family of transmembrane receptors that help to determine cell fate during development (8). In both vertebrates and invertebrates, NOTCH genes are expressed throughout the embryonal development in uncommitted or pre-committed proliferative cells (8). During fetal and adult development, expression of NOTCH continues in the proliferative layers of mature tissues (9,10).
The fully processed NOTCH receptors consist of an extracellular sub-unit (NEC) that is non-covalently bound to a transmembrane subunit (NTM) which includes the cytoplasmic domain (NIC). The N-terminal sequence of NIC contains the high-affinity interaction site for the transcription factor CBF1/RBP-Jkappa (11), which can regulate the IL-6 gene. Ligand-induced cleavage of the transmembrane subunit has been demonstrated in Drosophila and mammalian cells. This cleavage releases the entire intracellular portion of NOTCH which enters the nucleus and can interact with transcription factors such as CBF1 (FIG. 1).
Despite all the efforts by several teams/investigators to develop effective treatment for MM, this disease remains incurable. The treatments that are used in this disease allowed only limited efficacy in treating the disease. Conventional chemotherapy, mainly Melphalan, has been used extensively in the past, but when compared with allogeneic bone marrow transplantation (ABMT), only 14% of the patients reached complete remission (CR) as compared with ABMT with 38%. When high-dose chemotherapy is used, 22-30% CR is achieved. When combined with total body irradiation, 43% of CR and very good partial response is achieved. New therapeutic approaches are tested nowadays but they are all in phase I/II state. These compounds are Thalidomide and its derivatives (IMIs), protease inhibitor PS341-Velcade and Arsenic trioxide. However, the disease remains incurable. Available trials for some IMIds and PS341 show 71% (but only 13% of the patient showed a >75% reduction of paraprotein) and 47% (but only 30% of the patient showed a >75% reduction of paraprotein) of CR/PR, respectively. Accordingly, new approaches are needed for more effective treatment of plasma cell disorders.